Over 3 billion kg/yr of vinyl chloride (VC) are produced in the U.S. VC has been amply documented as a human carcinogen associated with liver haemoangiosarcoma and tumors of the brain and lungs. No mechanism for its tumorigenicity has emerged, even though tumors are easily induced in rodents, and VC and its mutagenic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) have been intensively studied. The known in vivo products of VC are three cyclic etheno bases, apparently derived from CAA; 7-(2-oxoethyl)G is apparently derived from CEO. Our long-term objective is to understand the molecular mechanism of initiation by VC, related carcinogens and their common metabolites. This approach has three specific aims: (1) To use physical, chemical, and biochemical methods to study three known etheno products (l,N6-etheno A, 3, N4-etheno C, and N2,3-etheno G) of VC- nucleic acid reaction in terms of effect on polymer structure, replication and fidelity. Special emphasis will be placed on N2,3- etheno G which can form two hydrogen bonds with C or T. (2) To investigate the formation of additional derivatives by epoxides and aldehydes, including several biologically important simple mono- and bifunctional agents (e.g., ethylene oxide, cyanoethylene oxide, chloroacetaldehyde). (3) To study the initial chemical steps in formation of cyclic derivatives and crosslinks by the aldehyde and halide functions of the VC metabolites. Our purpose is to search for biologically significant chemical events that could be mutagenic or lethal. The methods and approaches will utilize chemical synthesis of modified dNTPs, rNTPs, with and without radiolabel; kinetics and sequence of aldehyde/epoxide reactions; helix-coil transitions of polymers and oligomers containing modified etheno derivatives; optical methods (UV, IR, fluorescence); HPLC, gel electrophoresis, nucleotide sequencing; in vitro replication of defined oligomers; and utilization of etheno NTPs in site-directed mutagenesis.